Vesicular Stomatitis Virus-Based Vaccine Protects Hamsters against Lethal Challenge with Andes Virus

Andes virus (ANDV) and Sin Nombre virus (SNV) are the main causative agents responsible for hantavirus cardiopulmonary syndrome (HCPS) in the Americas. HCPS is a severe respiratory disease with a high fatality rate for which there are no approved therapeutics or vaccines available. Some vaccine approaches for HCPS have been tested in preclinical models, but none have been tested in infectious models in regard to their ability to protect against multiple species of HCPS-causing viruses. Here, we utilize recombinant vesicular stomatitis virus-based (VSV) vaccines for Andes virus (ANDV) and Sin Nombre virus (SNV) and assess their ability to provide cross-protection in infectious challenge models. We show that, while both rVSVΔG/ANDVGPC and rVSVΔG/SNVGPC display attenuated growth as compared to wild type VSV, each vaccine is able to induce a cross-reactive antibody response. Both vaccines protected against both homologous and heterologous challenge with ANDV and SNV and prevented HCPS in a lethal ANDV challenge model. This study provides evidence that the development of a single vaccine against HCPS-causing hantaviruses could provide protection against multiple agents.

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Antiviral Innate Responses Induced by VSV-EBOV Vaccination Contribute to Rapid Protection

mBio ◽

10.1128/mbio.00597-19 ◽

2019 ◽

Vol 10 (3) ◽

Cited By ~ 7

Author(s):

Andrea R. Menicucci ◽

Allen Jankeel ◽

Heinz Feldmann ◽

Andrea Marzi ◽

Ilhem Messaoudi

Keyword(s):

Gene Expression ◽

Vesicular Stomatitis Virus ◽

Cell Activation ◽

Ebola Virus ◽

Virus Disease ◽

Multiorgan Failure ◽

Ebola Virus Disease ◽

Phase Iii ◽

Lethal Challenge ◽

Vesicular Stomatitis

ABSTRACTEbola virus (EBOV) is a single-stranded RNA virus that causes Ebola virus disease (EVD), characterized by excessive inflammation, lymphocyte apoptosis, hemorrhage, and coagulation defects leading to multiorgan failure and shock. Recombinant vesicular stomatitis virus expressing the EBOV glycoprotein (VSV-EBOV), which is highly efficacious against lethal challenge in nonhuman primates, is the only vaccine that successfully completed a phase III clinical trial. Additional studies showed VSV-EBOV provides complete and partial protection to macaques immunized 7 and 3 days before EBOV challenge, respectively. However, the mechanisms by which this live-attenuated vaccine elicits rapid protection are only partially understood. To address this, we carried out a longitudinal transcriptome analysis of host responses in whole-blood samples collected from cynomolgus macaques vaccinated with VSV-EBOV 28, 21, 14, 7, and 3 days before EBOV challenge. Our findings indicate the transcriptional response to the vaccine peaks 7 days following vaccination and contains signatures of both innate antiviral immunity as well as B-cell activation. EBOV challenge 1 week after vaccination resulted in large gene expression changes suggestive of a recall adaptive immune response 14 days postchallenge. Lastly, the timing and magnitude of innate immunity and interferon-stimulated gene expression correlated with viral burden and disease outcome in animals vaccinated 3 days before challenge.IMPORTANCEEbola virus (EBOV) is the causative agent of Ebola virus disease (EVD), a deadly disease and major public health threat worldwide. A safe and highly efficacious vesicular stomatitis virus-based vaccine against EBOV is the only platform that has successfully completed phase III clinical trials and has been used in recent and ongoing outbreaks. Earlier studies showed that antibodies are the main mode of protection when this vaccine is administered 28 days before EBOV challenge. Recently, we showed this vaccine can provide protection when administered as early as 3 days before challenge and before antibodies are detected. This study seeks to identify the mechanisms of rapid protection, which in turn will pave the way for improved vaccines and therapeutics. Additionally, this study provides insight into host gene expression signatures that could provide early biomarkers to identify infected individuals who are at highest risk of poor outcomes.

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A single dose of a vesicular stomatitis virus-based influenza vaccine confers rapid protection against H5 viruses from different clades

npj Vaccines ◽

10.1038/s41541-019-0155-z ◽

2020 ◽

Vol 5 (1) ◽

Cited By ~ 12

Author(s):

Wakako Furuyama ◽

Pierce Reynolds ◽

Elaine Haddock ◽

Kimberly Meade-White ◽

Mai Quynh Le ◽

...

Keyword(s):

Influenza Virus ◽

Single Dose ◽

Vesicular Stomatitis Virus ◽

Severe Disease ◽

Lethal Dose ◽

H5n1 Influenza Virus ◽

Lethal Challenge ◽

H5n1 Influenza ◽

Vesicular Stomatitis ◽

Fast Acting

AbstractThe avian influenza virus outbreak in 1997 highlighted the potential of the highly pathogenic H5N1 virus to cause severe disease in humans. Therefore, effective vaccines against H5N1 viruses are needed to counter the potential threat of a global pandemic. We have previously developed a fast-acting and efficacious vaccine against Ebola virus (EBOV) using the vesicular stomatitis virus (VSV) platform. In this study, we generated recombinant VSV-based H5N1 influenza virus vectors to demonstrate the feasibility of this platform for a fast-acting pan-H5 influenza virus vaccine. We chose multiple approaches regarding antigen design and genome location to define a more optimized vaccine approach. After the VSV-based H5N1 influenza virus constructs were recovered and characterized in vitro, mice were vaccinated by a single dose or prime/boost regimen followed by challenge with a lethal dose of the homologous H5 clade 1 virus. We found that a single dose of VSV vectors expressing full-length hemagglutinin (HAfl) were sufficient to provide 100% protection. The vaccine vectors were fast-acting as demonstrated by uniform protection when administered 3 days prior to lethal challenge. Moreover, single vaccination induced cross-protective H5-specific antibodies and protected mice against lethal challenge with various H5 clade 2 viruses, highlighting the potential of the VSV-based HAfl as a pan-H5 influenza virus emergency vaccine.

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Recombinant vesicular stomatitis virus-based west Nile vaccine elicits strong humoral and cellular immune responses and protects mice against lethal challenge with the virulent west Nile virus strain LSU-AR01

Vaccine ◽

10.1016/j.vaccine.2008.11.087 ◽

2009 ◽

Vol 27 (6) ◽

pp. 893-903 ◽

Cited By ~ 29

Author(s):

Arun V. Iyer ◽

Bapi Pahar ◽

Marc J. Boudreaux ◽

Nobuko Wakamatsu ◽

Alma F. Roy ◽

...

Keyword(s):

West Nile Virus ◽

Immune Responses ◽

Vesicular Stomatitis Virus ◽

Virus Strain ◽

West Nile ◽

Lethal Challenge ◽

Cellular Immune Responses ◽

West Nile Virus Strain ◽

Vesicular Stomatitis ◽

Cellular Immune

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Attenuated Vesicular Stomatitis Viruses as Vaccine Vectors

Journal of Virology ◽

10.1128/jvi.73.5.3723-3732.1999 ◽

1999 ◽

Vol 73 (5) ◽

pp. 3723-3732 ◽

Cited By ~ 190

Author(s):

Anjeanette Roberts ◽

Linda Buonocore ◽

Ryan Price ◽

John Forman ◽

John K. Rose

Keyword(s):

Influenza Virus ◽

Vesicular Stomatitis Virus ◽

Neutralizing Antibodies ◽

Intranasal Administration ◽

Complete Protection ◽

Lethal Challenge ◽

Virus Challenge ◽

Influenza Virus Hemagglutinin ◽

Vesicular Stomatitis ◽

Ha Protein

ABSTRACT We showed previously that a single intranasal vaccination of mice with a recombinant vesicular stomatitis virus (VSV) expressing an influenza virus hemagglutinin (HA) protein provided complete protection from lethal challenge with influenza virus (A. Roberts, E. Kretzschmar, A. S. Perkins, J. Forman, R. Price, L. Buonocore, Y. Kawaoka, and J. K. Rose, J. Virol. 72:4704–4711, 1998). Because some pathogenesis was associated with the vector itself, in the present study we generated new VSV vectors expressing HA which are completely attenuated for pathogenesis in the mouse model. The first vector has a truncation of the cytoplasmic domain of the VSV G protein and expresses influenza virus HA (CT1-HA). This nonpathogenic vector provides complete protection from lethal influenza virus challenge after intranasal administration. A second vector with VSV G deleted and expressing HA (ΔG-HA) is also protective and nonpathogenic and has the advantage of not inducing neutralizing antibodies to the vector itself.

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Mapping the Interface between New World Hantaviruses and Their Receptor, PCDH1

Proceedings ◽

10.3390/proceedings2020050008 ◽

2020 ◽

Vol 50 (1) ◽

pp. 8

Author(s):

Megan M. Slough ◽

Andrew S. Herbert ◽

Ana I. Kuehne ◽

John M. Dye ◽

Kartik Chandran ◽

...

Keyword(s):

Viral Entry ◽

New World ◽

Point Mutations ◽

Hemorrhagic Fever ◽

Antiviral Drugs ◽

Lethal Challenge ◽

Hamster Model ◽

Binding Interface ◽

Andes Virus ◽

Vesicular Stomatitis

Hantaviruses are found throughout the world and can cause deadly diseases in humans, specifically, hantavirus cardiopulmonary syndrome (HCPS) in the New World and hemorrhagic fever with renal syndrome (HFRS) in the Old World. Currently, no FDA-approved, specific antiviral drugs or vaccines are available. Recently, we showed that New World hantaviruses utilize protocadherin-1 (PCDH1) for endothelial cell entry and infection by directly engaging its first extracellular cadherin repeat (EC1) domain. The knockout of PCDH1 also greatly reduced pulmonary infection and was highly protective in a Syrian hamster model of lethal challenge with Andes virus (ANDV). To further understand PCDH1’s role in hantavirus entry, we sought to map the binding interface between hantavirus Gn/Gc and PCDH1-EC1. Accordingly, we screened a panel of EC1 proteins, bearing point mutations in solvent-exposed residues, for their capacity to recognize Gn/Gc and block viral entry. EC1 mutations defective in Gn/Gc binding were engineered individually and in combinations into full-length PCDH1, expressed in PCDH1-knockout cells, and evaluated for their capacity to complement viral infection. We identified a surface in the PCDH1-EC1 domain, comprising contiguous residues, which was required for virus PCDH1 recognition and PCDH1-dependent viral entry. However, this region does not overlap with the EC1–EC4 heterodimer interface recently described by Modak and Sotomayor. In addition, through the use of recombinant vesicular stomatitis viruses bearing chimeric hantavirus Gn/Gc glycoproteins, we were able to pinpoint the importance of the N-terminal domain of the Gn subunit for PCDH1-mediated entry. With these taken together, identifying the location of the interface could provide a direction for the development of host-directed antiviral drugs that do not interfere with PCDH1’s endogenous function, as well as help to map an antigen target on Gn/Gc for antiviral antibodies.

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